Functional connectivity modifications in monoaminergic circuits occur in fatigued MS patients treated with fampridine and amantadine

Background Monoaminergic network dysfunction may have a role in multiple sclerosis (MS) fatigue pathogenesis. Objective To investigate modifications of fatigue severity and resting state (RS) functional connectivity (FC) in monoaminergic networks of 45 fatigued MS patients after different symptomatic treatments. Methods Patients were randomly, blindly assigned to fampridine ( n = 15), amantadine ( n = 15) or placebo ( n = 15) treatment and underwent clinical and 3T-MRI evaluations at baseline (t0) and week 4 (w4), i.e. after four weeks of treatment. Fifteen healthy controls (HC) were enrolled. Dopamine-, noradrenaline- and serotonin-related RS FC was assessed by PET-guided constrained independent component analysis. Results At t0, MS patients showed widespread monoamine-related RS FC abnormalities. At w4, fatigue scores decreased in all groups ( p = range < 0.001–0.002). Concomitantly, fampridine and amantadine patients showed increased insular RS FC in dopamine-related and noradrenaline-related networks ( p < 0.001, uncorrected). Amantadine patients also showed increased RS FC of anterior cingulate cortex in dopamine-related and noradrenaline-related networks ( p < 0.001, uncorrected). Placebo patients showed increased precuneus/middle cingulate RS FC in the noradrenaline-related network ( p < 0.001, uncorrected). In fampridine and placebo patients, just tendencies towards correlations between RS FC and fatigue modifications were found. Conclusions In MS patients, specific RS FC modifications in PET-guided monoaminergic networks were observed, concomitantly with fatigue improvements following treatment. Trial registration number EudraCT 2010-023678-38.